An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition

Philip A. Gregory, Cameron P. Bracken, Eric Smith, Andrew G. Bert, Josephine Wright, Suraya Roslan, Melanie Morris, Leila Wyatt, Gelareh Farshid, Yat Yuen Lim, Geoffrey J. Lindeman, M. Frances Shannon, Paul A. Drew, Yeesim Khew-Goodall, Gregory J. Goodall

Research output: Contribution to journalArticle

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Abstract

Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers.

LanguageEnglish
Pages1686-1698
Number of pages13
JournalMolecular Biology of the Cell
Volume22
Issue number10
DOIs
Publication statusPublished - 15 May 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Gregory, Philip A. ; Bracken, Cameron P. ; Smith, Eric ; Bert, Andrew G. ; Wright, Josephine ; Roslan, Suraya ; Morris, Melanie ; Wyatt, Leila ; Farshid, Gelareh ; Lim, Yat Yuen ; Lindeman, Geoffrey J. ; Shannon, M. Frances ; Drew, Paul A. ; Khew-Goodall, Yeesim ; Goodall, Gregory J. / An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. In: Molecular Biology of the Cell. 2011 ; Vol. 22, No. 10. pp. 1686-1698.
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abstract = "Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers.",
author = "Gregory, {Philip A.} and Bracken, {Cameron P.} and Eric Smith and Bert, {Andrew G.} and Josephine Wright and Suraya Roslan and Melanie Morris and Leila Wyatt and Gelareh Farshid and Lim, {Yat Yuen} and Lindeman, {Geoffrey J.} and Shannon, {M. Frances} and Drew, {Paul A.} and Yeesim Khew-Goodall and Goodall, {Gregory J.}",
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Gregory, PA, Bracken, CP, Smith, E, Bert, AG, Wright, J, Roslan, S, Morris, M, Wyatt, L, Farshid, G, Lim, YY, Lindeman, GJ, Shannon, MF, Drew, PA, Khew-Goodall, Y & Goodall, GJ 2011, 'An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition', Molecular Biology of the Cell, vol. 22, no. 10, pp. 1686-1698. https://doi.org/10.1091/mbc.E11-02-0103

An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. / Gregory, Philip A.; Bracken, Cameron P.; Smith, Eric; Bert, Andrew G.; Wright, Josephine; Roslan, Suraya; Morris, Melanie; Wyatt, Leila; Farshid, Gelareh; Lim, Yat Yuen; Lindeman, Geoffrey J.; Shannon, M. Frances; Drew, Paul A.; Khew-Goodall, Yeesim; Goodall, Gregory J.

In: Molecular Biology of the Cell, Vol. 22, No. 10, 15.05.2011, p. 1686-1698.

Research output: Contribution to journalArticle

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T1 - An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition

AU - Gregory, Philip A.

AU - Bracken, Cameron P.

AU - Smith, Eric

AU - Bert, Andrew G.

AU - Wright, Josephine

AU - Roslan, Suraya

AU - Morris, Melanie

AU - Wyatt, Leila

AU - Farshid, Gelareh

AU - Lim, Yat Yuen

AU - Lindeman, Geoffrey J.

AU - Shannon, M. Frances

AU - Drew, Paul A.

AU - Khew-Goodall, Yeesim

AU - Goodall, Gregory J.

PY - 2011/5/15

Y1 - 2011/5/15

N2 - Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers.

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